{"entity": "publication", "iuid": "c788a40c60dd4f9fadc15d4b13204a16", "timestamp": "2026-10-05T01:22:25.952Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/c788a40c60dd4f9fadc15d4b13204a16.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/c788a40c60dd4f9fadc15d4b13204a16"}}, "title": "Translatome analysis of tuberous sclerosis complex 1 patient-derived neural progenitor cells reveals rapamycin-dependent and independent alterations.", "authors": [{"family": "Aksoylu", "given": "Inci S", "initials": "IS"}, {"family": "Martin", "given": "Pauline", "initials": "P"}, {"family": "Robert", "given": "Francis", "initials": "F"}, {"family": "Szkop", "given": "Krzysztof J", "initials": "KJ"}, {"family": "Redmond", "given": "Nicholas E", "initials": "NE"}, {"family": "Bhattacharyya", "given": "Srirupa", "initials": "S"}, {"family": "Wang", "given": "Jennifer", "initials": "J"}, {"family": "Chen", "given": "Shan", "initials": "S"}, {"family": "Beauchamp", "given": "Roberta L", "initials": "RL"}, {"family": "Nobeli", "given": "Irene", "initials": "I"}, {"family": "Pelletier", "given": "Jerry", "initials": "J"}, {"family": "Larsson", "given": "Ola", "initials": "O"}, {"family": "Ramesh", "given": "Vijaya", "initials": "V"}], "type": "journal article", "published": "2023-10-25", "journal": {"title": "Mol Autism", "issn": "2040-2392", "volume": "14", "issue": "1", "pages": "39", "issn-l": null}, "abstract": "Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in the TSC1 or TSC2 genes, with patients often exhibiting neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD) and intellectual disability. Hamartin (TSC1) and tuberin (TSC2) proteins form a complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. Loss of TSC1 or TSC2 activates mTORC1 that, among several targets, controls protein synthesis by inhibiting translational repressor eIF4E-binding proteins. Using TSC1 patient-derived neural progenitor cells (NPCs), we recently reported early ND phenotypic changes, including increased cell proliferation and altered neurite outgrowth in TSC1-null NPCs, which were unaffected by the mTORC1 inhibitor rapamycin.\n\nHere, we used polysome profiling, which quantifies changes in mRNA abundance and translational efficiencies at a transcriptome-wide level, to compare CRISPR-edited TSC1-null with CRISPR-corrected TSC1-WT NPCs generated from one TSC donor (one clone/genotype). To assess the relevance of identified gene expression alterations, we performed polysome profiling in postmortem brains from ASD donors and age-matched controls. We further compared effects on translation of a subset of transcripts and rescue of early ND phenotypes in NPCs following inhibition of mTORC1 using the allosteric inhibitor rapamycin versus a third-generation bi-steric, mTORC1-selective inhibitor RMC-6272.\n\nPolysome profiling of NPCs revealed numerous TSC1-associated alterations in mRNA translation that were largely recapitulated in human ASD brains. Moreover, although rapamycin treatment partially reversed the TSC1-associated alterations in mRNA translation, most genes related to neural activity/synaptic regulation or ASD were rapamycin-insensitive. In contrast, treatment with RMC-6272 inhibited rapamycin-insensitive translation and reversed TSC1-associated early ND phenotypes including proliferation and neurite outgrowth that were unaffected by rapamycin.\n\nOur work reveals ample mRNA translation alterations in TSC1 patient-derived NPCs that recapitulate mRNA translation in ASD brain samples. Further, suppression of TSC1-associated but rapamycin-insensitive translation and ND phenotypes by RMC-6272 unveils potential implications for more efficient targeting of mTORC1 as a superior treatment strategy for TAND.", "doi": "10.1186/s13229-023-00572-3", "pmid": "37880800", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC10601155"}, {"db": "pii", "key": "10.1186/s13229-023-00572-3"}], "notes": [], "created": "2026-09-23T11:18:29.189Z", "modified": "2026-09-23T11:18:29.208Z"}